Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-05-19
1999-01-26
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544265, 544276, A61K 3152, C07D47318, C07D47330
Patent
active
058639217
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to purine and guanine derivatives and their use purine nucleoside phosphorylase (PNP) inhibitors, for treating conditions in mammals which are responsive to purine nucleoside phosphorylase inhibition.
BACKGROUND OF THE INVENTION
9-Arylmethyl-substituted purines (including guanines) have been reported as PNP inhibitors in EP-A-0, 178,178 substantially corresponding to U.S. Pat. No. 4,772,606. 9-Arylmethyl-substituted purines (including guanines), in which the aryl ring contains phosphonic acid groups, have also been reported as PNP inhibitors in EP-A-0,465,297 WO-A-92/05180. Modified purines, namely 9-deazapurines, have also been reported as PNP inhibitors in U.S. Pat. No. 4,985,434; U.S. Pat. No. 5,008,265; U.S. Pat. No. 4,985,433; U.S. Pat. No. 5,236,926; U.S. Pat. No. 5,236,926 and U.S. Pat. No. 5,008,270.
PNP inhibitory data cited in Drugs of the Future, 13, 654 (1988), Agents and Actions, 21, 253 (1987), Proc Natl Acad Sci USA, 88, 11540 (1991) and US 90/01021 indicate that modifications to the guanine base markedly alter the PNP inhibitory ability of such compounds. Also, modifications to the aryl ring of the 9-deaza (9-arylmethyl) purines can markedly alter PNP inhibitory activity. Namely replacement of a pyridine ring with piperidine greatly reduces activity as illustrated in IL Farmaco, 48 (2), 297 (1993).
SUMMARY OF THE INVENTION
The compounds of the invention are particularly useful in mammals as purine nucleoside phosphorylase (PNP) inhibitors, as selective inhibitors of T-cells and for suppressing cellular immunity. They can thus be used for the treatment of autoimmune diseases, transplant rejection, psoriasis or gout in mammals. They can also be used to potentiate the antiviral and antitumor effect of antiviral or antitumor purine nucleosides. tautomers, salts, solvates and hydrates. ##STR3## wherein
n=1-2;
R.sup.1 represents H or the group NH.sub.2 or halogen;
R.sup.2 represents H or the group NH.sub.2 ;
R.sup.3 represents the group ##STR4## where m=0,1
R.sup.4 and R.sup.5 may be the same or different and may be H or the group CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, NHSO.sub.2 CF.sub.3, tetrazole, (CR.sup.6 R.sup.7)p (Y)q (CR.sup.6 R.sup.7)tZ.
Where the group (CR.sup.6 R.sup.7)p or (CR.sup.6 R.sup.7)t may be straight or branched chain bearing the substituents R.sup.6 and R.sup.7 p and t>1.
R.sup.6 and R.sup.7 may be the same or different and may be H or the group C.sub.0-6 alkyl Z.
p=1-3
q=0,1
t=0-4
Y=NH, O, S(O)u where u=0-2
Z may be H or the group CN, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, NHSO.sub.2 CF.sub.3, tetrazole, triazole, CONH.sub.2, CON(C.sub.1-6 alkyl).sub.2, CONH(C.sub.1-6 alkyl), SO.sub.2 NH (C.sub.1-6 alkyl), SO.sub.2 N(C.sub.1-6 alkyl).sub.2.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds; thus t>0 when q=1.
DESCRIPTION OF THE INVENTION
The present invention includes all possible substitution patterns around the substituent R.sup.3, and may also include substitution by R.sup.4 at more than one carbon atom of the ring.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
In the formulae herein, the .about. line is used at a potential asymmetric centre to represent the possibility of R- and S- configurations, and the < line and the . . . line to represent a unique configuration at an asymmetric centre.
As used in this specification, alone or in combination, the term "C.sub.1-6 alkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like.
The term "ha
REFERENCES:
patent: 4895434 (1990-01-01), Segrist, III
Beasley Steven Colin
Manallack David Thomas
Montana John Gary
Berch Mark L.
Darwin Discovery Limited
LandOfFree
Purine and guanine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Purine and guanine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Purine and guanine derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1450662